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Tuesday, April 1, 2008

Chloroform provides clue to the enigma of general anaesthesia

One of the earliest general anaesthetics to be used by the medical profession, chloroform, has shed light on a mystery that’s puzzled doctors for more than 150 years – how such anaesthetics actually work.

A discovery described as “true serendipity” made by Leeds University PhD student Dr Yahya Bahnasi, has provided a clue that may unravel the enigma of general anaesthesia – and offer the opportunity to design new generations of anaesthetics without harmful side effects.

“We take general anaesthesia for granted nowadays, but it’s still true to say that we don’t know exactly how it works on a molecular level,” says Dr Bahnasi, a qualified medical doctor on an Egyptian Ministry of Higher Education Scholarship at the University’s Faculty of Biological Sciences.

“However, I was examining the relationship between lipids and atherosclerosis [the furring up of arteries] and it just so happened that the lipids I was using were supplied already dissolved in chloroform. I noticed that the chloroform inhibited, or blocked, the calcium ion channel TRPC5 – it was quite a striking effect.”

Ion channels are pathways that allow electrically charged atoms to pass across cell membranes to carry out various functions such as pain transmission and the timing of the heart beat. TRPC5 calcium ion channels are found in many tissues around the body but are predominant in the brain.

“We know that this ion channel plays a signalling role in the central nervous system, which regulates the conscious and unconscious states, so I was left wondering whether inhibiting this calcium ion channel was one mechanism by which anaesthesia works,” says Dr Bahnasi.

Dr Bahnasi then carried out further experiments with several other modern anaesthetic compounds, both intravenous and inhaled, and found that the blocking effect on the TRPC5 ion channel was the same.

He says that the discovery opens up the opportunity to design and develop new generations of anaesthetics which directly target TRPC5, but with minimised side effects.

“Of course there are multi-molecular events that work together in anaesthesia, and inhibiting the TRPC5 ion channel may just be one of them. But it’s a great start in piecing together the underlying mechanisms and providing a novel molecular target for new drug design,” he says. “And it’s particularly fitting that this evidence was revealed by chloroform, the ‘grandfather’ of modern anaesthetics.”

1. Yahya Bahnasi, 36, is a qualified medical doctor. He was awarded one of 25 medical scholarships funded annually by the Egyptian Government to study abroad. He is currently in his fourth year of a PhD, working in the research team of Professor David Beech, a reknowned world expert in ion channels, in the Institute of Membrane and Systems Biology.

2. Dr Bahnasi’s research was funded jointly by the Wellcome Trust and the Egyptian Government through his scholarship. The paper Modulation of TRPC5 cation channels by halothane, chloroform and propofol is published in the latest issue of the British Journal of Pharmacology. A copy of the paper is available on request.

3. Anaesthesia means ‘no sensation’ and a general anaesthetic adds unconsciousness to the lack of sensation. General anaesthesia is a multidimensional phenomenon that included unconsciousness, amnesia, analgesia, loss of sensory processing and the depression of movement.

4. Anaesthetics are unique in pharmacology as they are non-specific drugs. The only comparable drugs are disinfectants; for example, we use alcohols and phenols to clean injection sites; we do not use penicillin or other antibiotics for this purpose, because they bind to specific targets.

5 Chloroform has long been put out to pasture as a general anaesthetic, but its importance to the progression of surgery since its first recorded use in 1847 is enormous. Its popularity soared when Queen Victoria famously used it for the births of her youngest two children in the 1850’s, and between 1865 and 1920, chloroform was used in up to 95% of all operations performed in UK - despite its tendency to cause fatal cardiac arrhythmia. Its use had gradually petered out by the mid 20th century with the discovery of newer, safer compounds with fewer toxic side effects.

6. The Faculty of Biological Sciences at the University of Leeds is one of the largest in the UK, with over150 academic staff and over 400 postdoctoral fellows and postgraduate students. The Faculty has been awarded research grants totalling some £60M and funders include charities, research councils, the European Union and industry. Each of the major units in the Faculty has the highest Grade 5 rated research according to the last government (HEFCE) Research Assessment Exercise, denoting research of international standing. The Faculty is also consistently within the top three for funding from the government’s research councils, the BBSRC and NERC. www.fbs.leeds.ac.uk

7. The University of Leeds is one of the largest higher education institutions in the UK with more than 30,000 students from 130 countries. With a total annual income of £422m, Leeds is one of the top ten research universities in the UK, and a member of the Russell Group of research-intensive universities. It was recently placed 80th in the Times Higher Educational Supplement's world universities league table and the University's vision is to secure a place among the world's top 50 by 2015.

8. The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research in the UK and internationally, spending around £500 million each year to support the brightest scientists and the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. www.wellcome.ac.uk

9. campuspr is a public relations company that specialises in promoting university research and knowledge transfer. Working in partnership with the University’s press office, campuspr is contracted by the Faculties of Biological Sciences and Engineering at Leeds to promote the wealth of research projects, grants, new technologies and knowledge transfer activities that these faculties are actively engaged in. For more press releases, see www.campuspr.co.uk